Infertility is a complex and heterogeneous syndrome that affects 15% of all married couples. In a majority of infertile men the cause of infertility remains unknown. The treatment modalities are, therefore, empiric, unproven and often unsuccessful. There is reason to believe that a genetic basis of infertility may exist in a subset of infertile men currently classified as idiopathic. Based on a growing body of evidence, it is hypothesized that microdeletions in Yq deletion interval 6 account for a significant proportion of infertile men presenting with azoospermia or severe oligozoospermia and that gene/s in this region of the Y chromosome play a critical role in spermatogenesis and defects in these genes are associated with infertility in men. Although large deletions of the long arm of Y chromosome that are detectable on karyotype are undoubtedly uncommon in infertile men, it is not known what proportion of infertile men have Yq microdeletions. In this regard the specific objective of this project is to ascertain the prevalence of Yq microdeletions in a rigidly defined subset of infertile men presenting with azoospermia or severe oligozoospermia (sperm density less that 1 million/ml). We will recruit 100 infertile men who meet our Inclusion and Exclusion criteria. Peripheral blood lymphocytes from these patients and their family members will be immortalized by EBV transformation. Microdeletions will be detected by using polymerase chain reaction (PCR) amplification of sequence tagged-sites (STSs) on Yq deletion interval 6. The procedures for STS-mapping have been validated and standarized in our lab by inclusion of appropriate positive and negative controls in each PCR reaction. We will determine the deletion break points in men found to have Yq microdeletions; this will help delineate the consensus deletion interval. The testicular histology and the clinical characteristics of these patients will be correlated with the genetic defect to determine if specific phenotypes are associated with Yq microdeletions. Availability of a large sample of well characterized patients, multi-disciplinary nature of the investigating team that brings together experts from relevant disciplines and the use of a rational and validated molecular approach will maximize the chances of uncovering the pathogenetic basis of infertility in some defined subsets of men with "idiopathic infertility". A clear understanding of the underlying cause will inevitably facilitate efforts at developing specific therapies.